1. Field of the Invention
The present invention is directed to N-substituted-6-iodo-3,14-dihydroxy-4,5-.alpha.-epoxymorphinan, intermediates for producing the same, and methods of detecting the presence of opioid receptors.
2. Description of Related Art
Positron Emission Tomography (PET) and Single Photon Emission Computerized Tomography (SPECT) are non-invasive techniques for the direct visualization and quantitation of various parameters of brain function such regional cerebral blood flow and cerebral metabolism. The functional status and anatomical disposition of specific neuroreceptor systems can also be ascertained by the PET and SPECT methods. [.sup.18 F]cyclofoxy was developed as an agent for visualization of opioid receptors with PET. With this compound and PET, abnormalities of opioid receptor distribution in diseased states has been demonstrated. However, while PET is acknowledged as a useful state-of-the-art technique, it suffers substantial disadvantages which include high operating costs of the PET facility (a cyclotron is required), numerous personnel to man the facility, technical complexity of performing PET studies and very short half-lives for all positron emitting isotopes. The short half life of .sup.18 F and other positron emitting radioisotopes precludes their use in ligands which exhibit either a slow "on rate" or slow receptor localization. These and other disadvantages result in inadaptability of the technique to the small hospital setting and greater costs to the patient or third party care-providers.
Many of the problems associated with the short half life of positron emitting isotopes can be circumvented by a technique known as SPECT or single photon emission computerized tomography. SPECT was originally developed to study regional cerebral blood flow and cerebral perfusion and has been especially useful in examining differences in cerebral blood flow seen in Alzheimer's disease and depression. However, it has more recently been adapted to neurotransmitter systems. In SPECT studies, an .sup.123 I-labelled form of a drug or ligand is administered to subjects. .sup.123 I differs from positron emitting ligands in that it emits single monoenergetic x-ray photons, has a longer half life (13.2 hrs), and is considerably cheaper and easier to generate than for example .sup.18 F. Since SPECT does not rely on coincidence detection as does PET, the detector system is simpler and less expensive. The longer half life of .sup.123 I offers a longer time window for observation of the subjects, and often provides sufficient time for clearance of non-specific labelling where this is a problem. The resolution (7-8 mm) offered by recent generation SPECT scanners is close to that offered by PET (6 mm).
Cyclofoxy (6.beta.-fluoro-3,14-dihydroxy-17-cyclopropyl methyl-4,5.alpha.-epoxymorphinan, U.S. Pat. No. 4,775,759) was the first ligand available for PET imaging of opioid receptors. Cyclofoxy has been used successfully to image and quantitate brain opioid receptors via PET technology. Several human neurological and psychiatric disorders have already been investigated with cyclofoxy. However, because of the disadvantages associated with PET technology, such investigations have been restricted only to major research centers. Two other PET ligands that recognize the opiate receptor, [.sup.11 C] carfentanyl and [.sup.11 C] diprenorphine have been used to label opioid receptors in humans. Their use has been similarly restricted to major research centers that have PET facilities.
To date, no other SPECT ligands for imaging opioid receptors has been developed for use in humans. Imaging opioid receptors with SPECT has the potential to go beyond imaging the brain. Recently, opioid receptors have been found on human lung cancer cells. As a result, by using N-substituted-6-iodo-3,14-dihydroxy-4,5-.alpha.-epoxymorphinans in SPECT lung scans, it may be possible to visualize the receptors on cancer cells that are the targets for chemotherapy, and thus be useful to assess therapeutic response to lung cancer treatments.
The present invention has been accomplished in order to find useful SPECT ligands suitable for imaging tissue which have the opioid receptors present both in vivo and in vitro. The ability to measure opioid receptors in vivo in their unaltered or native state offers considerable advantages over tissue homogenization techniques which often alter properties of the opioid receptors.